Despite technical advances in neurosurgery, radiotherapy and the development of novel drugs, the outcome for malignant glioma patients has not improved during the last few decades. The development of effective delivery systems for therapeutics directly to brain tumors is critical for patients with malignant glioma. We believe replicons are an attractive alternative to the gene therapy vectors currently under evaluation. In this Phase I proposal, we propose to test the feasibility of replicons as a gene therapy vector for delivery of cytotoxic genes to tumor cells in vivo. A replicon expressing the reporter gene luciferase will first be used to establish the parameters of infection in vivo. Replicons encoding a suicide gene (HSV-TK) or cytotoxic genes (IL-4, TNF-alpha) will then be evaluated for the capacity to inhibit tumor growth and increase survival of tumor-bearing mice. The experiments proposed in these specific aims will establish the feasibility of using encapsidated replicons as vectors for the delivery of therapeutic molecules directly to brain tumors. These studies should establish the foundation to expand this proposal into a Phase II study with the goal of eventually bringing the encapsidated replicons to the marketplace as a vector for brain tumor therapies. PROPOSED COMMERCIAL APPLICATIONS: Although malignant brain tumors are diagnosed in approximately 15,000 American adults annually, with approximately 11,000 deaths each year, there has been little improvement in the outcome for these patients over the last few decades. Clearly, alternatives for treatment are necessary. We believe that replicons are a alternative treatment that, once developed, would have enormous commercial potential.